Endometriosis: Cellular and Molecular Mechanisms Leading to Fibrosis

Abstract

Endometriosis is a chronic inflammatory condition affecting women of reproductive age. A relevant feature of endometriosis is the presence of fibrotic tissue inside and around the lesions, thus contributing to the classic endometriosis-related symptoms, pain, and infertility. The molecular mechanisms responsible for the development of fibrosis in endometriosis are not yet defined. The present review aimed to examine the biological mechanisms and signalling pathways involved in fibrogenesis of endometriotic lesions, highlighting the difference between deep infiltrating and ovarian endometriosis. The main cell types involved in the development of fibrosis are platelets, myofibroblasts, macrophages, and sensory nerve fibers. Members of the transforming growth factor (TGF) -β family, as well as the receptor Notch, or the bioactive sphingolipid sphingosine 1-phosphate (S1P), play a role in the development of tissue fibrosis, resulting in their metabolism and/or their signalling pathways altered in endometriotic lesions. It is relevant the knowledge of the molecular mechanisms that guide and support fibrosis in endometriosis, to identify new drug targets and provide new therapeutic approaches to patients.

Keywords: Deep infiltrating endometriosis; Endometrioma; Endometriosis; Fibrosis; S1P; TGF-β.

Fig. 1

Main cellular types and molecules involved in the development of ovarian endometriosis − related fibrosis; COX-2, cyclooxygenase 2; CTGF, connective tissue growth factor; EGF: epithelial growth factor; EMT, epithelial to mesenchymal transition; EndoMT, endothelial to mesenchymal transition; IL-6, interleukin 6; OMA, ovarian endometrioma; S1P, sphingosine-1-phosphate; PAI-1, plasminogen activator inhibitor-1; PDGF, platelets derived growth factor; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor; Wnt, wingless-related integration site

Fig. 2

Principal cellular types and molecules implicated in the development of DIE-related fibrosis. DIE, deep infiltrating endometriosis; EMT, epithelial to mesenchymal transition; FMT, fibroblast to myofibroblast transition; IL-6, interleukin 6; IL-8, interleukin 8; MSTN, myostatin; SMM, smooth muscle metaplasia; SP, substance P; S1P, sphingosine-1-phosphate; PAI-1, plasminogen activator inhibitor-1; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor, Wnt, wingless-related integration site